tbuckley/cabot-search huggingface dataset:
Preliminary clinical outcomes of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in patients with advanced urothelial cancer.
Authors: David H Aggen, David S. Hong, Jeffrey Melson Clarke, Adam Steven Asch, Emiliano Calvo, Jon Zugazagoitia, Marcus O. Butler, Victor Moreno, Andres Cervantes, Brian Andrew Van Tine, Donald P. Lawrence, Melissa Lynne Johnson, Francine Elizabeth Brophy, Robyn Broad, Martin Isabelle, Alasdair Gunn, Jean-Marc Navenot, Jose Saro, Elliot Norry, John A. Charlson
Journal: Journal of Clinical Oncology (2023)

517 Background: ADP-A2M4CD8 is a specific peptide enhanced affinity receptor mixed CD4+ and CD8+ T-cell therapy targeting the cancer testis antigen MAGE-A4 and modified with addition of a CD8α co-receptor designed to provide additional functionality to CD4+ T-cells. ADP-A2M4CD8 has demonstrated an acceptable benefit to risk profile in the Phase 1 SURPASS trial (NCT04044859) in HLA A*02–eligible patients with unresectable or metastatic tumors positive for MAGE-A4. 1 Here we report updated clinical outcomes in patients with urothelial cancer (UC). Methods: SURPASS is a first-in-human trial consisting of a modified 3+3 dose-escalation design and an expansion cohort. Autologous T-cells are obtained by leukapheresis, transduced with a self-inactivating lentiviral vector expressing the MAGE-A4-specific T-cell receptor and the CD8α co-receptor, and infused back to the patients as ADP-A2M4CD8 following lymphodepleting chemotherapy. Primary and secondary objectives are safety and anti-tumor activity, respectively. Results: At ESMO 2022, we reported promising results from SURPASS in several tumour types. 2 In the 43 evaluable patients, the overall response rate was 28%, including 1 complete response and 11 partial responses (PR), and an additional 2 unconfirmed PRs awaiting confirmatory scans (as of August 1, 2022). Data from the 7 evaluable patients in the UC subset (updated September 6, 2022) showed that 3 (43%) had a best overall response of PR, and 1 (14%) had an unconfirmed PR. Disease control rate was 100% (3 PR + 1 unconfirmed PR + 3 stable disease). Adverse events have been consistent with those typically observed with lymphodepletion chemotherapy or cellular therapy. This trial is ongoing; data from additional patients with UC treated by January 2023 and updated translational data will be presented. Conclusions: ADP-A2M4CD8 continues to show an acceptable benefit to risk profile in multiple MAGE-A4+ unresectable or metastatic tumors, and preliminary encouraging evidence of efficacy in UC. An additional treatment cohort has been included in the updated trial protocol to evaluate ADP-A2M4CD8 combined with nivolumab. 1. Hong DS, et al. E-poster 540P: ESMO 2021; Virtual. 2. Hong DS, et al. Ann Oncol 33(suppl_7); S331-S355, Abstract 735MO. ESMO 2022. Clinical trial information: NCT04044859 .
Associations between patient sociodemographic factors and non-treatment for localized prostate cancer.
Authors: Madison Novosel, Shayan Smani, Victoria A. Marks, Farah Jeong, Preston Sprenkle, Michael Leapman
Journal: Journal of Clinical Oncology (2023)

307 Background: Although definitive treatment is associated with improved survival for aggressive prostate cancer, a significant number of patients do not receive treatment. To identify gaps in practice, we sought to evaluate sociodemographic factors associated with non-treatment by clinical risk strata in the contemporary era. Methods: We performed a retrospective study of patients with prostate cancer using the National Cancer Database. A total of 616,479 patients diagnosed with localized prostate (cT1-4N0M0) cancer from 2010 to 2017 were included in the analysis. We used descriptive statistics and multivariable logistic regression to evaluate factors associated with non-treatment, stratifying analyses by D’Amico clinical risk criteria. Results: The mean patient age at diagnosis was 65 years. 29.0% were diagnosed with low, 43.7% with intermediate, and 28.4% with high-risk prostate cancer. There were 71,848 (11.7%) who did not undergo initial treatment, including 46,269 (64.4%) with low, 18,376 (25.6%) with intermediate, and 7,203 (10.0%) with high-risk disease. Overall, non-treatment increased for low-risk (11.6% versus 47.0%), intermediate (4.4% versus 9.7%) and high risk (3.4% versus 4.7%). Compared with White patients, Black patients had lower odds of definitive treatment. This effect was more pronounced for patients with high (OR 0.63, 95% CI 0.59-0.67) than intermediate (OR 0.78, 95% CI 0.75-0.82) risk disease. Asian patients had lower odds of treatment compared with White patients across all disease risk strata (OR 0.82, 95% CI 0.77-0.87). There were lower odds of treatment among American Native/Alaskan Native versus White patients with high-risk prostate cancer (OR 0.58, 95% CI 0.39-0.85). Uninsured (OR 0.41, 95% CI 0.39-0.44, p&lt;0.001), and Medicaid-insured (OR 0.69, 95% CI 0.65-0.72, p&lt;0.001) patients were significantly less likely to be treated overall. The effects of Black race and non-treatment did not differ by insurance status (p-value for interaction=0.237). Conclusions: Patient race and insurance are significantly associated with non-treatment for aggressive prostate cancer.
Multicenter population-level analysis of systemic therapy use in metastatic or recurrent prostate cancer.
Authors: Heba Mohamed, Grace Kim, Corin Macphail, Ishmam Bhuiyan, Taylor Sidhu, Amir Emami, Longlong Huang, Shaun Zheng Sun, Scott Tyldesley, Jenny J. Ko
Journal: Journal of Clinical Oncology (2023)

89 Background: Treatment (tx) options for metastatic prostate cancer (mPC) have advanced significantly. There is a need for data in prescribing patterns and real-world survival outcomes of new therapeutics. Methods: We conducted chart review on all consecutive patients (pts) diagnosed with any stage of PC between 2016-2017 in British Columbia, and only included pts with de novo metastasis or later recurrence. We performed descriptive statistics, univariate and multivariate analysis to examine overall survival (OS). Results: This study included 796 pts with either de novo metastatic (n=554, 69.6%) or recurrent PC (N=242; 30.4 %); 743 (93.3%) had metastasis by time of cutoff (Sep 1, 2022). Median age at diagnosis of mPC in all patients was 73 (range 45-98). 790 (99.2%) started ADT. 263 (35.4%) had additional line of tx started with ADT at mCSPC; 309 (38.8%) had 1 st line tx started at mCRPC. 149 pts (18.7%) had testing for homologous repair defects (21 positive). Radiotherapy (RT) to prostate for mPC were given to 93 (11.6%). 307 (38.6%) received 1 line of tx; 181 (22.7%), 2; 128 (16.1%), 3 or more. 432 (54.3%) received &gt;=1 androgen receptor-axis-targeted therapies (ARAT). At cutoff, 474 (59.5%) died; most (n=400; 84.4%) died of prostate cancer. Pts who only stayed on ADT or who stayed on 1 additional tx had better OS than who had more than 1 line (NR vs. 55.5m vs. 21.0m, p=0.03). Similarly, pts who required no ARAT or stayed on 1 ARAT had longer OS than patients who had more than 1 ARAT (NR vs. 48.5m vs. 22.5m, p=0.009). No statistical difference in OS was seen between pts who had chemotx vs none, or pts on trial vs none. None of age, PSA at metastatsis, Gleason score, ADT type, RT to prostate or number of systemic tx were identified as an independent factor affecting OS on multivariate analysis. Pts with comorbidities (hypertension, CHF, diabetes, seizure, prior stroke, CAD or dementia) received abiraterone/prednisone, enzalutamide or apalutamide at a similar rate. Conclusions: Our multicenter data show low uptake of early treatment intensification in pts with mPC. Similar to other real-world data to date, pts who required less switch to another systemic tx were associated with better OS. Different ARATs were prescribed despite potential side effects at a similar rate to pts with major comorbidities.
Development and validation of a multi-institutional nomogram of outcomes for PSMA-PET–based salvage radiotherapy in recurrent prostate cancer.
Authors: Constantinos Zamboglou, Armelle Arnoux, Ali Janbain, Iosif Strouthos, Andrea Farolfi, Stefan Koerber, Jan Peeken, Marco Vogel, Konstantinos Ferentinos, Mohamed Shelan, Anca L. Grosu, Stephanie Kroeze, Matthias Guckenberger, Stefano Fanti, George Hruby, Sophia Scharl, Thomas Wiegel, Christoph Henkeberens, Louise Emmett, Nina-Sophie Hegemann
Journal: Journal of Clinical Oncology (2023)

355 Background: We aimed to develop and to validate a multi-institutional nomogram of outcomes for PSMA-PET based salvage radiotherapy (sRT) following radical prostatectomy (RP) for patients with recurrent or persistent prostate cancer (PCa). Methods: Data from patients with a detectable post-RP prostate-specific antigen (PSA) treated with sRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 11 academic institutions from 5 countries. All patients had a PSMA-PET scan prior sRT and patients with distant metastases on PET were excluded from this analysis. The freedom from biochemical failure (FFBF) rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse (BR) was defined as PSA nadir +0.2 ng/ml after sRT. Results: Overall, 1029 patients (training set n=821, external validation set n=208) with a median follow-up of 33 months were included. On PSMA-PET, 427 (42%) and 313 (30%) patients had local and nodal recurrences, respectively. Elective pelvic lymphatics were irradiated in 368 (36%) patients. All patients received sRT to the prostatic fossa receiving a dose of &lt;66 Gy, 66-70 Gy and &gt;70 Gy in 103 (10%), 551 (54%) and 375 (36%) patients, respectively. Androgen deprivation therapy (ADT) was given in 325 (32%) patients. On multivariable Cox regression analysis, pre-SRT PSA, ISUP grade, pT stage, surgical margins, ADT use, sRT dose and nodal recurrence on PSMA PET were associated with FFBF. The nomogram concordance index was 0.7 for FFBF in external validation. Conclusions: We present an externally validated contemporary nomogram which can estimate individual patient outcomes after PSMA-PET guided sRT. Positive lymph nodes on PSMA-PET seem to be a new risk factor for BR after sRT.
Impact of sarcomatoid features on treatment outcomes in metastatic clear cell renal cell carcinoma treated with first-line immunotherapy combinations.
Authors: Kelly N. Fitzgerald, Cihan Duzgol, Andrea Knezevic, Natalie Shapnik, Ritesh R Kotecha, David H Aggen, Maria Isabel Carlo, Neil J. Shah, Martin H Voss, Darren R. Feldman, Robert J. Motzer, Chung-Han Lee
Journal: Journal of Clinical Oncology (2023)

687 Background: The presence of sarcomatoid features in clear cell renal cell carcinoma (cRCC) has historically been associated with poor response to tyrosine kinase inhibitor (TKI) monotherapy and poor overall survival; however, immunotherapy (IO) combination therapies have shown more promise in treating this variant. Front-line anti-PD-1 based IO combinations used in ccRCC include ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted TKI with a PD-1 inhibitor (TKI/IO). Here, we compare progression-free survival after therapeutic 1st-line (PFS) and 2nd-line (PFS-2) in patients who received IO/IO vs TKI/IO combinations as 1st line treatment for metastatic ccRCC, and test whether the treatment effects differ based on the presence or absence of sarcomatoid dedifferentiation. Methods: A retrospective analysis was performed on patients with ccRCC initiating 1 st line combination IO at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020. Patient cohorts were defined by 1 st line treatment type: IO/IO or TKI/IO. PFS and PFS-2 were estimated using the Kaplan-Meier method. Restricted mean survival time (RMST) was calculated for PFS and PFS-2 in each 1 st line treatment group and modelled using a generalized linear model adjusted for IMDC risk. To test for heterogeneity of treatment effect among subgroups, sarcomatoid features (presence/absence) is included in the models and an interaction test is performed. Results: Ninety patients (28 sarcomatoid) received 1 st line IO/IO and 83 (17 sarcomatoid) received 1 st line TKI/IO. Median PFS time is 6.8 months (95% CI: 4.5, 12.2) for IO/IO and 21 months (95% CI: 15, 25) for TKI/IO, p=0.009. After adjusting for IMDC risk, and after 48 months of follow-up, RMST for PFS was 10 months for IO/IO and 24 months for TKI/IO (p=0.02) and RMST for PFS-2 was 20 months for IO/IO and 23 months for TKI/IO (p=0.24). In the RMST model, the interaction between treatment group and presence or absence of sarcomatoid features is not significant for PFS (0.95) or PFS-2 (0.29). Conclusions: For ccRCC patients treated with 1 st line IO/IO or TKI/IO, adjusted RMST for PFS was significantly longer for the TKI/IO group, but there was no statistically significant difference in adjusted RMST for PFS-2. Anti-PD-1-based therapy is an effective approach to treating ccRCC with sarcomatoid features. [Table: see text]
Impact of systemic therapy (ST) on deferred cytoreductive nephrectomy (CN) perioperative outcomes: A National Surgical Quality Improvement Program (NSQIP) analysis.
Authors: Shawn Dason, Tyler Sheetz, Shagnik Ray, Danielle Elise Zimmerman, Ming Yin, Edmund Folefac, Amir Mortazavi, Michael Gong, Ahmad Shabsigh, Eric A. Singer
Journal: Journal of Clinical Oncology (2023)

650 Background: Management of metastatic renal cell carcinoma (mRCC) is highly individualized and often involves cytoreductive nephrectomy (CN) and systemic therapy (ST). The optimal sequencing of CN and ST is uncertain. A difference in perioperative outcomes based on sequence of CN and ST could influence decision-making. We conducted this NSQIP analysis to assess whether preoperative systemic therapy adversely impacted perioperative outcomes in patients receiving deferred CN. Methods: This analysis was conducted using the American College of Surgeons NSQIP Participant Use Data File for years 2019 and 2020. These years were selected because data on receipt of preoperative therapy is only available since 2019. Inclusion criteria were i) CPT code consistent with nephrectomy, ii) urologist operating surgeon &amp; iii) presence of disseminated cancer. All cases with ICD-10 diagnosis codes not consistent with mRCC were excluded. Groups were stratified by their receipt of preoperative systemic therapy within 90 days before CN and we assessed 46 preoperative and perioperative outcomes. Results: The study cohort included 505 patients with 115 (23%) who received preoperative ST. No differences were noted in perioperative outcomes (Table). Patients receiving preoperative ST were more likely to be on steroids (23% vs. 7%, p&lt;0.01) and develop urinary tract infections (4.3% vs. 0.5%, p&lt;0.01). There were no significant differences noted in other related variables like surgical site infections, wound dehiscence, sepsis, septic shock, pneumonia, cardiovascular complications, preoperative hypertension, or preoperative diabetes (p&gt;0.05). Conclusions: Because preoperative ST did not have an appreciable impact on deferred CN perioperative outcomes, decision making for ST and CN sequencing should not be influenced by perioperative outcomes. Those who undergo deferred CN are unlikely to experience delayed time to surgery or perioperative complications from their ST. [Table: see text]
ECOG score as a barrier for clinical trial eligibility in the patient population with genitourinary cancer: Is it time to adapt this criterion to real-world data?
Authors: Limor Gortzak Uzan, Lena Lapidot, Tzvia Bader, Avital Gaziel
Journal: Journal of Clinical Oncology (2023)

78 Background: ECOG score is a common eligibility criteria used in clinical trials (CT). Many CT recruit only patients in good physical condition (ie. minimal comorbidities and good performance status), which may misrepresent the real-world cancer population.This gap may result in safety and effectiveness data that may not be applicable to the real-world patient population. Furthermore, applying strict eligibility criteria augment a barrier for patient accrual to CT. In this study we analyzed the impact of ECOG performance status on Genitourinary (GU) oncology trials eligibility of patients who used the Trialjectory web-based platform. Methods: Trialjectory is an AI- based platform that matches cancer patients to CT based on a patient reported questionnaire that translates to an individual clinical profile. The profile includes disease status and stage, biomarkers, treatment history and comorbidities and demographics. Data from patients with prostate and urinary bladder cancer was analyzed. The number of matched trials per patient was determined based on the patient’s profile, location and travel preference. To assess the impact of ECOG score, we edited the data set to reflect a better performance status per patient. We used a paired samples Wilcoxon test to assess the association between decreasing the ECOG threshold and the number of matched CT. Results: Between May 2021 and August 2022 we analyzed 153 bladder cancer profiles with ECOG=2 and 71 with ECOG=3, and 90 and 27 prostate cancer profiles with ECOG=2 and ECOG=3, respectively. In a multiple regression analysis, high ECOG score was inversely and significantly associated with the number of matched trials per patient in prostate cancer (p=0.009), independent of cancer stage, patient ethnicity and gender; and in urinary bladder cancer (p=0.003), after adjustment for cancer stage, gender and ethnicity. Editing ECOG score from 2 to 1 resulted in a profound increase (233% for prostate cancer patients and 300% for urinary bladder cancer patients respectively) in the number of matched trials per patient, from a median of 3 trials to 7 and from 2 to 6 trials per patient respectively (V = 426, p-value &lt;0.0001 and V = 14, p-value = 0.0002 respectively). Among Bladder Cancer patients, editing the ECOG score from 3 to 2 resulted in an increase of 200%, from a median 1 to 2 matched CT (V = 291, p-value = 0.0002). Conclusions: The results reflect a high magnitude reduction in eligibility for patients with higher ECOG scores. Excluding these patients may result in skewed reporting on effectiveness-toxicity of drugs that may not be applicable for the real-world patient population augmenting a significant barrier for CT accrual amongst the proactive population who seek it.
Clinical applications of urine- and blood-based genome wide copy number study from 1,000 patients with bladder and prostate cancer.
Authors: Chao Dai, Tiantian Zheng, Wei Mo, Giancarlo Bonora, Amy Wang, Shujun Luo, Kemin Zhou, Shidong Jia, Pan Du
Journal: Journal of Clinical Oncology (2023)

459 Background: Liquid biopsy has become increasingly important in cancer diagnosis and disease progression monitoring. Copy number variation is an important characteristic for genitourinary cancer and many other cancer types, where bladder cancer was shown to have the largest copy number alternation among 33 human cancer types from TCGA. We developed PredicineCNB, a companion LP-WGS assay to robustly estimate genome-wide copy number burden (CNB) from plasma and urine clinical samples, which can provide longitudinal disease monitoring in a cost-effective way. Methods: By integrating both fragments coverage and fragments length from LP-WGS data, and quantifying copy number deviation at chromosome arm level, we greatly increase both sensitivity and specificity for CNB based cancer detection. Analytical evaluation was performed based on clinical plasma titration samples, and PredicineCNB has demonstrated high cancer detection sensitivity (LOD is 1%) with high specificity (&gt; 99%), using DNA input amounts as low as 1ng. We also validated CNB using Predicine panel-based tumor fraction for more than 200 clinical samples, results demonstrated both are highly concordant with correlation coefficient 0.84. Results: We performed clinical evaluation of PredicineCNB on 700 patients with prostate cancer and 300 patients with bladder cancer. For clinical patients with longitudinal samples under different disease stages or drug treatments, we demonstrated a promising potential using PredicineCNB for monitoring dynamic changes in ctDNA, that are caused by copy number variation. For 12 different bladder cancer patients, each with at least two longitudinal samples, we observed that CNB declines as early as two weeks after treatment initiation, providing an early signal of molecular response to therapy. In addition, when comparing conventional radiology-based imaging with CNB, we found that an increase in CNB preceded clinical progression of disease in majority of patients; and CNB shows a positive correlation between cancer stage revealed by CT scan. Conclusions: We conducted a comprehensive clinical study using PredicineCNB in 1,000 patients with prostate and bladder cancers, demonstrating the promising clinical application of liquid biopsy-based genome-wide copy number changes in therapy monitoring.
Using microfluidic models to evaluate whether monocyte preconditioning plays a role in tumor-associated macrophage mediated resistance to hormone therapy in men with prostate cancer.
Authors: David Kosoff, Matthew L Bootsma, Shuang Zhao, Emma Recchia, Matthew T Breneman
Journal: Journal of Clinical Oncology (2023)

228 Background: While men with metastatic castrate-resistant prostate cancer benefit greatly from 2 nd generation androgen targeted therapies (ATTs), the utility of these therapies is inevitably limited by the development of resistance. Tumor associated macrophages (TAMs) are a myeloid immune cell population within the prostate tumor microenvironment (TME) that have been shown to play an integral role in development of ATT-resistance. However, the pathways that underlie TAM-mediated ATT resistance remain under investigation. In particular, many TAMs within the TME are derived from circulating monocytes and it is not yet clear whether the pathways driving TAM-mediated resistance are activated exclusively within the TME or if the activation of critical resistance pathways begins while the cells are circulating as monocytes. In this study, we utilized novel microscale technologies to investigate the transcriptome of monocytes and macrophages derived from patients progressing and responding to ATTs as well as the degree to which the macrophages promote ATT resistance in prostate tumor models. Methods: Primary monocytes were isolated from 22 men with prostate cancer who were either progressing or responding to 2 nd generation ATTs. A portion of the monocytes from each patient were isolated for transcriptome analysis and the rest were differentiated into monocyte-derived macrophages (MDMs). MDMs were then cultured in monoculture or in co-culture with androgen-independent prostate tumor cells (22Rv1 and C42B). Each culture was then left untreated or treated with enzalutamide therapy. Following culture/treatment, each macrophage condition was isolated for transcriptome analysis and tumor cell populations from each condition were evaluated for treatment cytotoxicity. Results: Viability data from MDM-C42B co-culture demonstrated a 20% increase in tumor cell viability following enzalutamide treatment when C42B cells were cultured with primary MDMs from castrate-sensitive patients as compared to MDMs from castrate-resistant patients. Subsequent transcriptome analysis demonstrated key signatures in monocyte/macrophage populations that were associated ATT response. Conclusions: Leveraging a novel microfluidic culture platform known as Stacks, we were able to utilize primary, patient-derived cells to demonstrate that the role of TAMs in ATT resistance within the prostate TME is dependent, at least in part, on factors that are present prior to extravasation into the TME. Transcriptome analysis identified candidate pathways, which may be driving TAM-mediated differences in ATT response. These findings have the potential to lead to future use of circulating monocytes as a predictive biomarker as well as lead to the identification and targeting of ATT resistance pathways in patients.